Endothelin receptor antagonists

ABSTRACT

This invention relates to derivatives of furan and thiophene, their composition, process of making and method of use as endothelin receptor antagonists.

This application claims the benefit of Provisional Application Ser. No.60/010,983 filed Feb. 1, 1996 and Provisional Application Ser. No.60/001,793 filed Aug. 2, 1995.

FIELD OF INVENTION

The present invention relates to furans and thiophenes pharmaceuticalcompositions containing these compounds and their use as endothelinreceptor antagonists.

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesizedand released by the vascular endothelium. Endothelin exists as threeisoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated "endothelin"shall mean any or all of the isoforms of endothelin]. Endothelin hasprofound effects on the cardiovascular system, and in particular, thecoronary, renal and cerebral circulation. Elevated or abnormal releaseof endothelin is associated with smooth muscle contraction which isinvolved in the pathogenesis of cardiovascular, cerebrovascular,respiratory and renal pathophysiology. Elevated levels of endothelinhave been reported in plasma from patients with essential hypertension,acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis,and patients with uraemia undergoing dialysis.

In vivo, endothelin has pronounced effects on blood pressure and cardiacoutput. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in ratscauses a transient, dose-related depressor response (lasting 0.5 to 2minutes) followed by a sustained, dose-dependent rise in arterial bloodpressure which can remain elevated for 2 to 3 hours following dosing.Doses above 3 nmol/kg in a rat often prove fatal.

Endothelin appears to produce a preferential effect in the renalvascular bed. It produces a marked, long-lasting decrease in renal bloodflow, accompanied by a significant decrease in GFR, urine volume,urinary sodium and potassium excretion. Endothelin produces a sustainedantinatriuretic effect, despite significant elevations in atrialnatriuretic peptide. Endothelin also stimulates plasma renin activity.These findings suggest that ET is involved in the regulation of renalfunction and is involved in a variety of renal disorders including acuterenal failure, cyclosporine nephrotoxicity, radio contrast induced renalfailure and chronic renal failure.

Studies have shown that in vivo, the cerebral vasculature is highlysensitive to both the vasodilator and vasoconstrictor effects ofendothelin. Therefore, ET may be an important mediator of cerebralvasospasm, a frequent and often fatal consequence of subarachnoidhemorrhage.

ET also exhibits direct central nervous system effects such as severeapnea and ischemic lesions which suggests that ET may contribute to thedevelopment of cerebral infarcts and neuronal death.

ET has also been implicated in myocardial ischemia (Nichols et al. Br.J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res., 65:1193-1200, 1989) coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165:301-304, 1989 and Luscher, Circ. 83: 701, 1991) heart failure,proliferation of vascular smooth muscle cells, (Takagi, Biochem &Biophys. Res. Commun.; 168: 537-543, 1990, Bobek et al., Am. J. Physiol.258:408-C415, 1990) and atherosclerosis, (Nakaki et al., Biochem. &Biophys. Res. Commun. 158: 880-881, 1989, and Lerman et al., New Eng. J.of Med. 325: 997-1001, 1991). Increased levels of endothelin have beenshown after coronary balloon angioplasty (Kadel et al., No. 2491 Circ.82: 627, 1990).

Further, endothelin has been found to be a potent constrictor ofisolated mammalian airway tissue including human bronchus (Uchida etal., Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20:343-348, 1990; and Springall et al., Lancet, 337: 697-701, 1991).Endothelin may play a role in the pathogenesis of interstitial pulmonaryfibrosis and associated pulmonary hypertension, Glard et al., ThirdInternational Conference on Endothelin, 1993, p. 34 and ARDS (AdultRespiratory Distress Syndrome), Sanai et al., Supra, p. 112.

Endothelin has been associated with the induction of hemorrhagic andnecrotic damage in the gastric mucosa (Whittle et al., Br. J. Pharm. 95:1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al., Lancet 337:114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al.,Lancet, Vol. 339, p. 381; Migraine (Edmeads, Headache, February 1991 p127); Sepsis (Weitzberg et al., Circ. Shock 33: 222-227, 1991; Pittet etal., Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failureor hypertension (Eur. J. Pharmacol., 180: 191-192, 1990, Kidney Int, 37:1487-1491, 1990) and endotoxin shock and other endotoxin induceddiseases (Biochem. Biophys. Res. Commun., 161: 1220-1227, 1989, ActaPhysiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases.(Clin Res. 41:451 and 484, 1993).

Endothelin has also been implicated in preclampsia of pregnancy. Clarket al., Am. J. Obstet. Gynecol. March 1992, p. 962-968; Kamor et al., N.Eng. J. of Med., Nov. 22, 1990, p. 1486-1487; Dekker et al., Eur J. Ob.and Gyn. and Rep. Bio. 40 (1991) 215-220; Schiff et al., Am. J. Ostet.Gynecol. February 1992, p. 624-628; diabetes mellitus, Takahashi et al.,Diabetologia (1990) 33:306-310; and acute vascular rejection followingkidney transplant, Watschinger et al., Transplantation Vol. 52, No. 4,pp. 743-746.

Endothelin stimulates both bone resorption and anabolism and may have arole in the coupling of bone remodeling. Tatrai et al. Endocrinology,Vol. 131, p. 603-607.

Endothelin has been reported to stimulate the transport of sperm in theuterine cavity, Casey et al., J. Clin. Endo and Metabolism, Vol. 74, No.1, p. 223-225, therefore endothelin antagonists may be useful as malecontraceptives. Endothelin modulates the ovarian/menstrual cycle,Kenegsberg, J. of Clin. Endo. and Met., Vol. 74, No. 1, p. 12, and mayalso play a role in the regulation of penile vascular tone in man, Lauet al., Asia Pacific J. of Pharm., 1991, 6:287-292 and Tejada et al., J.Amer. Physio. Soc. 1991, H1078-H1085. Endothelin also mediates a potentcontraction of human prostatic smooth muscle, Langenstroer et al., J.Urology, Vol. 149, p. 495-499.

Thus, endothelin receptor antagonists would offer a unique approachtoward the pharmacotherapy of hypertension, acute and chronic renalfailure, ischemia induced renal failure, sepsis-endotoxin induced renalfailure, prophylaxis and/or treatment of radio-contrast induced renalfailure, acute and chronic cyclosporin induced renal failure,cerebrovascular disease, stroke, subarachnoid hemorrhage,cerebrovascular spasm, myocardial ischemia, angina, congestive heartfailure, acute coronary syndrome, myocardial salvage, unstable angina,asthma, primary pulmonary hypertension, pulmonary hypertension secondaryto intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon,ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin inducedmultiple organ failure or disseminated intravascular coagulation,cyclosporin-induced renal failure and as an adjunct in angioplasty forprevention of restenosis, diabetes, diabetic retinopathy, retinopathy,diabetic nephropathy, diabetic macrovascular disease, atherosclerosis,preclampsia of pregnancy, bone remodeling, kidney transplant, malecontraceptives, infertility and priaprism and benign prostatichypertrophy.

SUMMARY OF THE INVENTION

This invention comprises compounds represented by Formula (I) andpharmaceutical compositions containing these compounds, and their use asendothelin receptor antagonists which are useful in the treatment of avariety of cardiovascular and renal diseases including but not limitedto: hypertension, acute and chronic renal failure, cyclosporine inducednephrotoxicity, benign prostatic hypertrophy, pulmonary hypertension,migraine, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm,myocardial ischemia, angina, congestive heart failure, atherosclerosis,diabetic nephropathy, diabetic retinopathy, retinopathy, diabeticmacrovascular disease, atherosclerosis and as an adjunct in angioplastyfor prevention of restenosis.

This invention further constitutes a method for antagonizing endothelinreceptors in an animal, including humans, which comprises administeringto an animal in need thereof an effective amount of a compound ofFormula (I).

In a further aspect the present invention provides a process for thepreparation of a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by structural Formula(I): ##STR1## D is O or S; P is tetrazol-5-yl, CO₂ R₆ orC(O)N(R₆)S(O)_(q) R₁₀ ;

R^(a) is independently hydrogen or C₁₋₆ alkyl;

R₁ is independently hydrogen, Ar, C₁₋₆ alkyl or C₁₋₆ alkoxy;

R₂ is Ar, C₁₋₈ alkyl, C(O)R₁₄ or ##STR2## R₃ and R₅ are independentlyR₁₃ OH, C₁₋₈ alkoxy, S(O)_(q) R₁₁, N(R₆)₂, NO₂, Br, F, I, Cl, CF₃,NHCOR₆, R₁₃ CO₂ R₇, --X--R₉ --Y, --X(C(R₆)₂)OR₆, --(CH₂)_(m) X'R₈ or--X(CH₂)_(n) R₈ wherein each methylene group within --X(CH₂)_(n) R₈ maybe unsubstituted or substituted by one or two --(CH₂)_(n) Ar groups;

R₄ is independently R₁₁, OH, C₁₋₅ alkoxy, S(O)_(q) R₁₁, N(R₆)₂, Br, F,I, Cl or NHCOR₆, wherein the C₁₋₅ alkoxy may be unsubstituted orsubstituted by OH, methoxy or halogen;

R₆ is independently hydrogen or C₁₋₈ alkyl;

R₇ is independently hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈alkynyl, all of which may be unsubstituted or substituted by one or moreOH, N(R₆)₂, CO₂ R₁₂, halogen or XC₁₋₁₀ alkyl; or R₇ is (CH₂)_(n) Ar;

R₈ is independently R₁₁, CO₂ R₇, CO₂ C(R₁₁)₂ O(CO)XR₇, PO₃ (R₇)₂, SO₂NR₇ R₁₁, NR₇ SO₂ R₁₁, CONR₇ SO₂ R₁₁, SO₃ R₇, SO₂ R₇, P(O)(OR₇)R₇, CN,CO₂ (CH₂)_(m) C(O)N(R₆)₂, C(R₁₁)₂ N(R₇)₂, C(O)N(R₆)₂, NR₇ C(O)NR₇ SO₂R₁₁, OR₆, or tetrazole which is substituted or unsubstituted by C₁₋₆alkyl;

R₉ is independently a bond, C₁₋₁₀ alkylene, C₁₋₁₀ alkenylene, C₁₋₁₀alkylidene, C₁₋₁₀ alkynylene, all of which may be linear or branched, orphenylene, all of which may be unsubstituted or substituted by one ofmore OH, N(R₆)₂, COOH or halogen;

R₁₀ is independently C₁₋₁₀ alkyl, N(R₆)₂ or Ar;

R₁₁ is independently hydrogen, Ar, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, all of which may be unsubstituted or substituted by one or moreOH, CH₂ OH, N(R₆)₂ or halogen;

R₁₂ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl;

R₁₃ is independently divalent Ar, C₁₋₁₀ alkylene, C₁₋₁₀ alkylidene,C₂₋₁₀ alkenylene, all of which may be unsubstituted or substituted byone or more OH, CH₂ OH, N(R₆)₂ or halogen;

R₁₄ is independently hydrogen, C₁₋₁₀ alkyl, XC₁₋₁₀ alkyl, Ar or XAr;

R₁₅ is independently C₁₋₆ alkyl or phenyl substituted by one or two C₁₋₆alkyl, OH, C₁₋₅ alkoxy, S(O)_(q) R₆, N(R₆)₂, Br, F, I, Cl, CF₃ or NHCOR₆;

X is independently (CH₂)_(n), O, NR₆ or S(O)_(q) ;

X' is independently O, NR₆ or S(O)_(q) ;

Y is independently CH₃ or X(CH2)_(n) Ar;

Ar is: ##STR3## naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl,morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all ofwhich may be unsubstituted or substituted by one or more Z₁ or Z₂groups;

A is independently C═O, or (C(R6)₂)_(m) ;

B is independently --CH₂ -- or --O--;

Z₁ and Z₂ are independently hydrogen, XR₆, C₁₋₈ alkyl, (CH₂)_(q) CO₂ R₆,C(O)N(R₆)₂, CN, (CH₂)_(n) OH, NO₂, F, Cl, Br, I, N(R₆)₂, NHC(O)R₆,O(CH₂)_(m) C(O)NR_(a) SO₂ R₁₅, (CH₂)_(m) OC(O)NR_(a) SO₂ R₁₅, O(CH₂)_(m)NR_(a) C(O)NR_(a) SO₂ R₁₅ or tetrazolyl which may be substituted orunsubstituted by C₁₋₆ alkyl, CF₃ or C(O)R₆ ;

m is independently 1 to 3;

n is independently 0 to 6;

q is independently 0, 1 or 2;

provided R₃, R₄ and R₅ are not O--O(CH₂)_(n) Ar or O--OR₆ ;

or a pharmaceutically acceptable salt thereof.

All alkyl, alkenyl, alkynyl and alkoxy groups may be straight orbranched.

Halogen may be Br, Cl, F or I.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeform. All of these compounds and diastereoisomers are contemplated to bewithin the scope of the present invention.

Preferred compounds are those wherein:

P is CO₂ R₆ ; more preferably P is CO₂ H.

R₁ is hydrogen.

R₂ is Ar, cyclohexyl or C₁₋₄ alkyl. More preferably R₂ is a group Arwherein Ar is a group (a) or (b). In said group (a) or (b) Z₁ and Z₂ areindependently hydrogen, CO₂ R₆, (CH₂)_(n) OH, C₁₋₄ alkyl or C₁₋₆ alkoxy,e.g. methoxy; A is preferably CH₂, and one or both Bs are preferably O.

R₃ and R₅ are independently hydrogen, CO₂ R₆, OH, C₁₋₈ alkoxy, C₁₋₈alkyl, N(R₆)₂, NO₂, Br, F, Cl, I, R₁₃ CO₂ R₇, X(CH₂)_(n) R₈, (CH₂)_(m)X'R₈, or X(C(R₆)₂)_(m) OR₆ ;

In the context of the group R₃ and R₅ preferably do not representhydrogen. In particular in the group R₃ preferably represents Br, Cl, Cg₈ alkoxy e.g. methoxy; X(CH₂)_(n) R₈, wherein X preferably representsO, n is 0, 1, or 2, and R₈ is preferably selected from:

CO₂ R₆ wherein R₆ is preferably hydrogen;

OR₆ wherein R₆ is preferably H;

tetrazolyl optionally substituted by C₁₋₈ alkyl e.g. ethyl;

CONR₇ SO₂ R₁₁ wherein R₇ is H or C₁₋₈ alkyl e.g. methyl, R₁₁ preferablyis C₁₋₈ alkyl (e.g. methyl, isopryl, or t-butyl) or phenyl optionallysubstituted by Br, Cl, F, C₁₋₈ alkyl e.g. methyl;

or R₈ is phenyl or pyridyl substituted by one or more Br, Cl, CO₂ H, CH₂OH.

R₅ is C₁₋₈ alkoxy e.g. methoxy, or N(R₆)₂ wherein R₆ preferably is H ormethyl.

R₄ is hydrogen, OH, C₁₋₅ alkoxy, N(R₆)₂, Br, F, Cl, I, NHCOCH₃, orS(O)_(q) C₁₋₅ alkyl wherein the C₁₋₅ alkyl may be unsubstituted orsubstituted by OH, methoxy or halogen. R₄ is more preferably hydrogen;

R₆ is hydrogen or C₁₋₈ alkyl e.g. methyl and ethyl;

R₇ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, all of whichmay be unsubstituted or substituted by one or more OH, N(R₆)₂, CO₂ R₁₂,halogen, or R₇ is (CH₂)_(n) Ar. When R₇ is (CH₂)_(n) Ar, n is preferablyzero or 1 and Ar is preferably phenyl substituted or unsubstituted byhalogen or C₁₋₅ alkoxy.

R₁₁ is hydrogen, phenyl, pyridyl wherein the phenyl and pyridyl may besubstituted or unsubstituted by one or two C₁₋₄ alkyl groups; C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, all of which may be substituted orunsubstituted by one or more OH, CH₂ OH, N(R₆)₂, or halogen;

R₁₂ is hydrogen or C₁₋₆ alkyl.

R₁₃ is phenyl, pyridyl, or C₂₋₁₀ alkylene, all of which may beunsubstituted or substituted by one or more CO₂ R₆, OH, CH₂ OH, N(R₆)₂,or halogen;

R₁₅ is preferably hydrogen or C₁₋₆ alkyl e.g. ethyl, isopropyl, n-butyl,cyclopropylmethyl or cyclopropylethyl.

The preferred compounds are:

E-3-[3-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylfur-2-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoicacid,E-3-[3-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylthien-2-yl]-2-[2-methoxy-4,5-methylenedioxy]methyl-prop-2-enoicacid and

E-3-[4-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylfur-3-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoicacid.

The present invention provides compounds of Formula (I). ##STR4## whichcan be prepared by a process which comprises: treating an aryl halide ofFormula (2) ##STR5## with an appropriate alkyllithium reagent such asn-butyllithium in tetrahydrofuran followed by addition of a borate suchas triisopropyl borate and acidic work up affords a boronic acid ofFormula (3) ##STR6## Reaction of a boronic acid of Formula (3) with acompound of Formula (4) ##STR7## in the presence of a suitable base suchas potassium carbonate with a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) in a mixture of toluene,ethanol and water at approximately 80-100° C. provides a compound ofFormula of (II) ##STR8## A compound of Formula (4) may be prepared froma dibromide of Formula (6) by ##STR9## monohalogen-metal exchange usingan appropriate alkyllithium reagent such as n-Butyllithium intetrahydrofuran followed by addition of an alkylating agent (eg.N,N-dimethylformate or R^(a) COCl).

Knoevenagel condensation of an aldehyde of Formula (II) with a half acidof Formula (7) ##STR10## in a solvent such as benzene at reflux, in thepresence of piperidinium acetate with azeotropic removal of water usinga Dean-Stark apparatus, affords an ester of Formula (8) ##STR11##Saponification of an ester of Formula (8) using aqueous sodium hydroxidein a solvent such as ethanol provides, after acidification with aqueoushydrochloric acid, an acid of Formula (I), wherein P═COOH.

The invention also is a process for preparing compounds of Formula (I)by:

(a) Reaction of a compound of Formula (II) ##STR12## or a protected formor precursor thereof (as defined hereinafter) with a compound of Formula(7) ##STR13## (wherein R₂ is defined for Formula (I) hereinabove);followed if necessary or desired by:

(b) conversion of one compound of Formula (I) into a different compoundof Formula (I) e.g.

(i) when Formula (I) contains a group CO₂ R₆, CO₂ R₇ or CO₂ R₁₂ whereinR₆, R₇ or R₁₂ is alkyl, conversion to a corresponding compound where R₆,R₇ or R₁₂ represents hydrogen;

(ii) when Formula (I) contains a hydroxy group (e.g. in R₃, R₄ or R₅)conversion to a different group, e.g. a group (CH₂)Ar where Ar isoptionally substituted phenyl, by method well known in the art; and/or

(c) salt formation.

It will be appreciated by those skilled in the art that thesubstitutents R₃, R₄, R₅ ; and Z₁ and Z₂ may be introduced at anyappropriate stage of the synthesis, preferably at an early stage, usingmethods well known in the art. In some of the reactions depicted above,particularly those in the early stages of the overall synthesis, one ormore of the substitutents may therefore represent a precursor for theeventual substituent. A precursor for any of the substitutents means agroup which may be derivatised or converted into the desired group. Itwill be further appreciated that it may be necessary or desirable toprotect certain of these substitutents(or their precursors) at variousstages in the reaction sequence. Suitable precursors and protectinggroups are well known to those skilled in the art, as are methods fortheir conversion or removal respectively.

In order to use a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

Compounds of Formula (I) and their pharmaceutically acceptable salts maybe administered in a standard manner for the treatment of the indicateddiseases, for example orally, parenterally, sub-lingually,transdermally, rectally, via inhalation or via buccal administration.

Compounds of Formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules and lozenges. A syrup formulation will generally consist of asuspension or solution of the compound or salt in a liquid carrier forexample, ethanol, peanut oil, olive oil, glycerine or water with aflavouring or colouring agent. Where the composition is in the form of atablet, any pharmaceutical carrier routinely used for preparing solidformulations may be used. Examples of such carriers include magnesiumstearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid,starch. lactose and sucrose. Where the composition is in the form of acapsule, any routine encapsulation is suitable, for example using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous or non-aqueous carrieroptionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered as a dry powder or inthe form of an aerosol using a conventional propellant such asdichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (1) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous ornon-aqueous vehicle, for example a cream, ointment, lotion or paste orare in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer tothemselves a single dose.

Each dosage unit for oral administration contains suitably from 0.1 mgto 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg, of a compound of Formula (I) or a pharmaceutically acceptable saltthereof calculated as the free acid. Each dosage unit for intranasaladministration contains suitably 1-400 mg and preferably 10 to 200 mgper person. A topical formulation contains suitably 0.01 to 1.0% of acompound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to40 mg/Kg, of a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for intranasal administration and oral inhalation is suitablyabout 10 to about 500 mg/person. The active ingredient may beadministered from 1 to 6 times a day, sufficient to exhibit the desiredactivity.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.

The biological activity of the compounds of Formula (I) are demonstratedby the following tests:

I. Binding Assay

A) CHO cell membrane preparation.

CHO cells stably transfected with human ET_(A) and ET_(B) receptors weregrown in 245 mm×245 mm tissue culture plates in Dulbecco's modifiedEagle's medium supplemented with 10% fetal bovine serum. The confluentcells were washed with Dulbecco's phosphate-buffered saline containing aprotease inhibitor cocktail (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml ofleupeptin and 0.1 U/ml of aprotinin) and scraped in the same buffer.After centrifugation at 800×g, the cells were lysed by freezing inliquid nitrogen and thawing on ice followed by homogenization (30 timesusing a glass dounce homogenizer) in lysis buffer containing 20 mM TrisHCl, pH 7.5, and the protease inhibitor cocktail. After an initialcentrifugation at 800×g for 10 min to remove unbroken cells and nuclei,the supernatants were centrifuged at 40,000×g for 15 min and the pelletwas resuspended in 50 mM Tris HCl, pH 7.5, and 10 mM MgCl₂ and stored insmall aliquots at -70° C. after freezing in liquid N₂. Protein wasdetermined by using the BCA method and BSA as the standard.

(B) Binding studies.

[¹²⁵ I]ET-1 binding to membranes prepared from CHO cells was performedfollowing the procedure of Elshourbagy et al. (1993). Briefly, the assaywas initiated in a 100 ul volume by adding 25 ul of [¹²⁵ I]ET-1 (0.2-0.3nM) in 0.05% BSA to membranes in the absence (total binding) or presence(nonspecific binding) of 100 nM unlabeled ET-1. The concentrations ofmembrane proteins were 0.5 and 0.05 ug per assay tube for ET_(A) andET_(B) receptors, respectively. The incubations (30° C., 60 min) werestopped by dilution with cold buffer (20 mM Tris HCl, pH 7.6, and 10 mMMgCl₂) and filtering through Whatman GF/C filters (Clifton, N.J.)presoaked in 0.1% BSA. The filters were washed 3 times (5 ml each time)with the same buffer by using a Brandel cell harvester and were countedby using a gamma counter at 75% efficiency.

The following examples are illustrative and are not limiting of thecompounds of this invention.

EXAMPLE 1(E)-4-n-Butyl-3-[[2-(2-carboxyphenyl)methoxy-4-methoxyphenyl]thiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-prop-2-enoicacid

a) 3-Bromo-4-butylthiophene

To a stirred solution of 3,4-dibromothiophene (4.60 g, 20.90 mmol) indry Et₂ O (50 mL) at -78° C. was dropwise added n-BuLi (2.5 M, 16.72 mL,41.80 mmol) under Ar. After stirring for 15 min, a solution of freshlydistilled di-n-butyl sulfate in dry Et₂ O (10 mL) was dropwise addedthrough an addition funnel. The mixture was allowed to warm to roomtemperature and stirred overnight. 30 mL of 12 M NH₄ OH was added to themixture. After stirring for 1 h, the mixture was partitioned between H₂O and Et₂ O. The organic layer was separated and washed with H₂ O, brineand dried (MgSO₄). Removal of the solvent under reduced pressureafforded the title compound as an oil (2.50 g, 60%).

b) 3-Bromo-4-n-butylthiophene-2-carboxaldehyde

To a solution of freshly prepared LDA (11.40 mmol) in THF (7 mL) at -78°C. was added slowly 3-bromo-4-butylthiophene of Example l(a) (2.50 g,11.40 mmol) in THF (10 mL). After stirring for 15 min, DMF (0.94 mL,12.10 mmol) in THF (2 mL) was dropwise added. The resulting mixture wasstirred for 1 h at -78° C. and then allowed to warm to room temperature.The reaction was quenched with water and extracted with EtOAc (2×50 mL).The combined organic extracts were washed with H₂ O, brine and dried(MgSO₄). After removing the solvent under reduced pressure, columnchromatography (silica gel, EtOAc/Hexane, 20:80) of the residue affordedthe title compound as an oil (1.87 g, 60%).

c)4-n-Butyl-3-(2-methoxymethoxy-4-methoxyphenyl)thiophene-2-carboxaldehyde

To a solution of 3-Bromo-4-n-butylthiophene-2-carboxaldehyde of Example1(b) 1.87 g, 7.57 mmol) in toluene (35 mL) was added (PPh₃)₄ Pd (0.30 g,0.20 mmol), Na₂ CO₃ (2 M, 9 mL), EtOH (25 mL) and(2-methoxymethoxy-4-methoxyphenyl)boronic acid (1.76 g, 8.30 mmol),respectively. The resulting mixture was stirred at reflux for 3 h. Afterquenching with water and extraction with EtOAc, the organic extract waswashed with H₂ O, brine and dried (MgSO₄). The solvent was removed underreduced pressure and column chromatography (silica gel, EtOAc/Hexane,25:75) of the residue afforded the title compound as an oil (1.80 g,71%)

d) Ethyl(E)-3-[4-n-butyl-3-(2-methoxymethoxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

4-n-Butyl-3-(2-methoxymethoxy-4-methoxyphenyl)thiophene-2-carboxaldehydeof Example 1(c) (1.05 g, 3.15 mmol), diethyl2-(2-methoxy-4,5-methylenedioxybenzyl)-malonate (1.25 g, 4.12 mmol),piperidine (0.10 mL, 1.1 mmol) and AcOH (0.11 mL, 1.80 mmol) weredissolved in benzene (30 mL) and refluxed with azetropic removal ofwater overnight. The solvent was removed under reduced pressure andcolumn chromatography (silica gel, EtOAc/Hexane, 30:70) of the residueafforded the title compound as an oil (0.80 g, 45%).

e) Ethyl(E)-3-[4-n-butyl-3-(2-hydroxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

To a solution of Ethyl(E)-3-[4-n-butyl-3-(2-methoxymethoxy-4-methoxyphenyl)-thiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoateof Example 1(d) (0.80 g, 1.41 mmol) in MeOH (20 L) was added 0.5 mL ofconc. HCl. The mixture was refluxed for 2 h, and then the solvent wasremoved under reduced pressure. The residue was partitioned between H₂ Oand EtOAc, and the organic layer was separated and washed with H₂ O,brine and dried (MgSO₄). After removing the solvent, columnchromatography (silica gel, EtOAc/Hexane, 30:70) of the residue gave thetitle compound as an oil (0.65 g, 87%).

f) Ethyl(E)-3-[4-n-butyl-3-[2-(2-methoxycarbonyl)phenylmethoxy-4-methoxyphenyl)]-thiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

To a solution of Ethyl(E)-3-[4-n-butyl-3-(2-hydroxy-4methoxy)phenylthiophen-3-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoateof Example 1(e) (0.65 g, 12.30 mmol) in DMF (5 mL) was added theprewashed NaH (0.64 g, 16.00 mmol) at 0° C. After stirring for 10 minmethyl 2-(bromomethyl) benzoate (0.32 g, 14.70 mmol) was added. Theresulting mixture was stirred for 2 h at room temperature and thenpartitioned between EtOAc and 5% HCl. The organic layer was separated,washed with H₂ O, brine and dried (MgSO₄). After removing the solventunder reduced pressure column chromatography (silica gel, EtOAC/Hexane,30:70) of the residue to afforded the title compound as an oil (0.65 g,78%).

g) (E)3-[4-n-Butyl-3-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-prop-2-enoicacid

To a solution of the ester of Example 1 (f) (0.65 g, 0.96 mmol) in EtOH(30 mL) was added 1 mL of aqueous NaOH (0.19 g, 4.80 mmol) and themixture was heated at reflux for 2 h. The reaction was quenched with 5%HCl and the resulting mixture was extracted with EtOAc (3×30 mL). Thecombined organic extracts were washed with H₂ O, brine and dried(MgSO₄). After removing the solvent under reduced pressure, theresulting residue was crystallized upon standing. Recrystallization fromEtOAc/Hexane (1:2) gave the title compound as white solid (0.28g, 46%):mp 165-167° C. ¹ H NMR (400 MHz ,DMSO-d₆) δ0.70 (t, J=7.20 Hz, 3H),1.08-1.15 (m,2H), 1.29-1.37 (m, 2H), 2.28-2.35(m, 2H), 3.28-3.40(br.,2H), 3.80 (s, 6H), 5.40-5.49 (m, 2H) 5.88 (s, 2H), 6.29 (s, 1H), 6.61(d, J=2.3 Hz, 1H), 6.70 (dd, J=2.3, 8.4 Hz, 1H), 6.80 (s, 1H), 7.09 (d,J=8.4 Hz), 7.26 (br. d, 1H), 7.35-7.42 (m, 2H), 7.43 (s, 1H), 7.71 (s,1H), 7.93 (br.d, 1H) Anal. Calcd for C₃₅ H₃₄ SO₉ : C,66.65; H, 5.43.Found: C 66.31; H, 5.54.

EXAMPLE 2(E)-3-[3-[(2-Carboxyphenyl)methoxy-4-methoxy]phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methlenedioxyphenyl)methyl]-prop-2-enoicacid

a) 3-(2-Methoxymethoxy-4-methoxyphenyl)thiophene-2-carboxaldehyde

Following the procedure of Example 1(c), but substituting3-Bromo-4-n-butylthiophene-2-carboxaldehyde with 3-bromothiophene, thetitle compound was prepared in 89% yield.

b) Ethyl(E)-3-[3-(2-methoxymethoxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

Following the procedure of Example 1(d), but subsituting4-n-Butyl-3-(2-methoxymethoxy-4-methoxyphenyl)thiophene-2-carboxaldehydewith 3-(2-methoxymethoxy-4-methoxy)phenylthiophene-2-carboxaldehyde, thetitle compound was prepared in 33% yield.

c) Ethyl(E)-3-[3-(2-hydroxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

Following the procedure of Example 1(e), but subsitituting Ethyl(E)-3-[4-n-butyl-3-(2-methoxymethoxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoatewith Ethyl(E)-3-[3-(2-methoxymethoxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate,the title compound was prepared in 41% yield.

d) Ethyl(E)-3-[3-(2-methoxycarbonylphenyl-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

Following the procedure of Example of 1(f), but subsitituting Ethyl(E)-3-[4-n-butyl-3-(2-hydroxy-4-methoxy)phenylthiophen-3-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoatewith Ethyl(E)-3-[3-(2-hydroxy-4-methoxy)phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate,the title compound was prepared in 75% yield.

e)(E)-3-[3-[2-(2-Carboxyphenyl)methoxy-4-methoxy]phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methlenedioxy)phenylmethyl]-prop-2-enoicacid

Following the procedure of Example 1(g), but subsitituting Ethyl(E)-3-[4-n-butyl-3-[2-(2-methoxycarbonyl)phenylmethoxy-4-methoxy]phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoatewith Ethyl(E)-3-[3-[2-(2-methoxycarbonyl)phenylmethoxy-4-methoxy]phenylthiophen-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate,the title compound was prepared as a white solid in 60% yield. mp228-231° C. (400 MHZ, CDCl₃) δ3.70 (s,2H), 3.82 (s,3H), 3.84 (s,3H),5.56 (s, 2H), 6.45 (s, 1H), 6.53 (s, 1H), 6.63 (dd, J=2.0, 8.30 Hz, 1H),6.72 (d, J=1.8 Hz, 1H), 7.14 (d, J=5.0 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H),7.33-7.43 (m, 1H), 7.43 (d, J=5.0 Hz, 1H), 7.49 (s, 1H), 7.49 (d, J=3.5Hz, 1H), 8.0 (s, 1H), 8.08 (d, J=7.5 Hz, 1H). Anal. Calcd for C₃₁ H₂₆SO₉.0.25H₂ O:C, 64.30; H,4.61. Found: C, 64.20; H, 4.65.

EXAMPLE 3(E)-3-[3-[2-(2-Carboxyphenyl)methoxy-4-methoxy]phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-prop-2-enoicacid

a) 3-Bromofuran-2-carboxaldehyde

To a solution of freshly prepared LDA (6.80 mmol) in THF (4 mL) at -78°C. was added slowly 3-bromofuran (1.00 g, 6.80 mmol) in THF (5 mL).After stirring for 15 min, DMF (0.56 mL, 7.20 mmol) in THF (2 mL) wasdropwise added. The resulting mixture was stirred for 1 h at -78° C. andthen allowed to warm to room temperature. The reaction was quenched withwater and extracted with EtOAc (2×50 mL). The combined organic extractswere washed with H₂ O, brine and dried (MgSO₄). After removing thesolvent under reduced pressure, column chromatography (silica gel,EtOAc/Hexane, 20:80) of the residue afforded the title compound as anoil (0.49 g, 41%).

b) 3-(2-Methoxymethoxy-4-methoxy)phenylfuran-2-carboxaldehyde

To a solution of 3-bromofuran-2-carboxaldehyde of Example 3(a) (0.40 g,1.29 mmol) in toluene (25 mL) was added (PPh₃)₄ Pd (0.09 g, 0.06 mmol),Na₂ CO₃ (2 M, 3 mL), EtOH (7 mL) and2-methoxymethoxy-4-methoxyphenylboronic acid (0.29 g, 2.75 mmol),respectively. The resulting mixture was stirred at reflux for 2 h. Afterquenching with water and extraction with EtOAc, the organic extract waswashed with H₂ O, brine and dried (MgSO₄). The solvent was removed underreduced pressure and column chromatography (silica gel, EtOAc/Hexane,25:75) of the residue afforded the title compound as an oil (0.60 g,100%)

c) Ethyl(E)-3-[3-(2-methoxymethoxy-4-methoxy)phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

3-(2-Methoxymethoxy-4-methoxy)phenylfuran-2-carboxaldehyde of Example3(b) (0.62 g, 2.37 mmol), diethyl2-(2-methoxy-4,5-methylenedioxybenzyl)-malonate (0.93 g, 3.10 mmol),piperidine (0.10 mL, 1.10 mmol) and AcOH (0.07 mL, 1.20 mmol) weredissolved in benzene (30 mL) and refluxed with azetropic removal ofwater overnight. The solvent was removed under reduced pressure andcolumn chromatography (silica gel, EtOAc/Hexane, 30:70) of the residueafforded the title compound as an oil (0.42 g, 36%).

d) Ethyl(E)-3-[3-(2-hydroxy-4-methoxy)phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

Ethyl(E)-3-[3-(2-methoxymethoxy-4-methoxy)phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoateof Example 3(c) (0.43 g, 0.85 mmol) in MeOH (20 mL) was added 0.5 mL ofconc. HCl. The mixture was refluxed for 2 h, and then the solvent wasremoved under reduced pressure. The residue was partitioned between H₂ Oand EtOAc. The organic layer was separated and washed with H₂ O, brineand dried (MgSO₄). After removing the solvent, column chromatography(silica gel, EtOAc/Hexane, 30:70) of the residue gave the title compoundas an oil (0.16 g, 41%).

e) Ethyl(E)-3-[3-(2-methoxycarbonyl)phenylmethoxy-4-methoxy)phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate

To a solution of Ethyl (E)-3-[3-(2-hydroxy-4-methoxy)phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoateof Example 3(d) (0.16 g, 0.35 mmol) in DMF (5 mL) was added theprewashed NaH (0.02 g, 0.53 mmol) at 0° C. After stirring for 10 minmethyl 2-(bromomethyl) benzoate (0.09 g, 0.42 mmol) was added. Theresulting mixture was stirred for 2 h at room temperature and thenpartitioned between EtOAc and 5% HCl. The organic layer was separated,washed with H₂ O, brine and dried (MgSO₄). After removing the solventunder reduced pressure, column chromatography (silica gel, EtOAC/Hexane,30:70) of the residue afforded the title compound as an oil (0.25 g,97%).

f)(E)-3-[3-[2-(2-Carboxyphenyl)methoxy-4-methoxy]phenylfuran-2-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoicacid

To a solution of the ester of Example 3(e) (0.21 g, 0.34 mmol) in EtOH(20 mL) was added 1 mL of aqueous NaOH (0.07 g, 1.70 mmol) and themixture was heated at reflux for 2 h. The reaction was quenched with 5%HCl and the resulting mixture was extracted with EtOAc (3×30 mL). Thecombined organic extracts were washed with H₂ O, brine and dried(MgSO₄). After removing the solvent under reduced pressure, theresulting residue was crystallized upon standing. Recrystallization fromEtOAc/Hexane (1:2) gave the title compound as white solid (0.09 g, 47%):mp 212-215° C. ¹ H NMR (400 MHz ,DMSO-d₆) δ3.73 (s, 3H), 3.81 (s, 3H),3.93 (s, 2H), 5.47 (s, 2H) 5.89 (s, 2H), 6.40 (s, 1H), 6.69-6.75 (m,2H), 6.27 (s, 2H), 7.21 9d, J=2.0 Hz, 1H), 7.42-7.45 (m, 1H), 7.46 (s,1H), 7.53-7.58 (m, 2H), 7.81 (d, J=1.71 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).Anal. Calcd for C₃₁ H₂₆ O₁₀.0.25H₂ O:C, 66.13; H,4.74. Found: C, 66.12;H, 4.73.

EXAMPLE 4

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.

Inhalant Formulation

A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metereddose inhaler to deliver the desired amount of drug per use.

    ______________________________________                                        Tablets/Ingredients   Per Tablet                                              ______________________________________                                        1.        Active ingredient                                                                             40    mg                                                       (Cpd of Form. I)                                                     2.    Corn Starch                                   20 mg                     3.    Alginic acid                                  20 mg                     4.    Sodium Alginate                               20 mg                     5.    Mg stearate                         1.3 mg                                                                               2.3 mg                     ______________________________________                                    

Procedure for tablets:

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitablemixer/blender.

Step 2 Add sufficient water portion-wise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3 The wet mass is converted to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 140° F. (60° C.)until dry.

Step 5 The dry granules are lubricated with ingredient No. 5.

Step 6 The lubricated granules are compressed on a suitable tabletpress.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is preparedby dissolving an appropriate amount of a compound of formula I inpolyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is then steriledby filtration through a 0.22 micron membrane filter and sealed insterile containers.

We claim:
 1. A compound of Formula (I): ##STR14## D is O; P is CO₂ R₆ orC(O)N(R₆)S(O)_(q) R₁₀ ;R^(a) is independently hydrogen or C₁₋₆ alkyl, R₁is independently hydrogen, Ar, C₁₋₆ alkyl, or C₁₋₆ alkoxy; R₂ is Ar,C₁₋₈ alkyl, C(O)R₁₄ or ##STR15## R₃ and R₅ are independently hydrogenCO₂, R₆, OH, R₁₃ OH, C₁₋₈ alkoxy, C₁₋₈ alkyl, S(O)_(q) R₁₁, N(R₆)₂, NO₂,Br, F, I, Cl, CF₃, NHCOR₆, R₁₃ CO₂ R₇, --X--R₉ --Y, --X(CR₆)₂)OR₆,(CH₂)_(m) XR₈ or --X(CH₂)_(n) R₈ wherein each methylene group within--X(CH₂)_(n) R₈ may be unsubstitutcd or substituted by one or two--(CH₂)_(n) Ar groups; R₄ is independently R₁₁, OH, C₁₋₅ alkoxy,S(O)_(q) R₁₁, wherein R₁₁ is C₁₋₅ alkyl is may be unsubstituted orsubstiteted by OH, methoxy, or halogen; N(R₆)₂, Br, F, I, Cl or NHCOR₆,wherein the C₁₋₅ alkoxy may be unsubstituted or substituted by OH,methoxy or halogen; R₆ is independently hydrogen or C₁₋₈ alkyl; R₇ isindependently hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, allof which may be unsubstituted or substituted by one or more OH, N(R₆)₂,CO₂ R₁₂, halogen or XC₁₋₁₀ alkyl; or R₇ is (CH₂)_(n) Ar; R₈ isindependently R₁₁, CO₂ R₇, CO₂ C(R₁₁)₂ O(CO)XR₇, PO₃ (R₇)₂, SO₂ NR₇ R₁₁,NR₇ SO₂ R₁₁, CONR₇ SO₂ R₁₁, SO₃ R₇, SO₂ R₇, P(O)(OR₇)R₇, CN, CO₂(CH₂)_(m) C(O)N(R₆)₂, C(R₁₁)₂ N(R₇)₂, C(O)N(R₆)₂, NR₇ C(O)NR₇ SO₂ R₁₁,OR₆ ; R₉ is independently a bond, C₁₋₁₀ alkylene, C₁₋₁₀ alkenylene,C₁₋₁₀ alkylidene, C₁₋₁₀ alkynylene, all of which may be linear orbranched, or phenylene, all of which may be unsubstituted or substitutedby one of more OH, N(R₆)₂, COOH or halogen; R₁₀ is independently C₁₋₁₀alkyl, N(R₆)₂ or Ar; R₁₁ is independently hydrogen, Ar, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, all of which may be unsubstituted or substitutedby one or more OH, CH₂ OH, N(R₆)₂ or halogen; R₁₂ is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl; R₁₃ is independentlydivalent Ar, C₁₋₁₀ alkylene, C₁₋₁₀ alkylidene, C₂₋₁₀ alkenylene, all ofwhich may be unsubstituted or substituted by one or two CO₂ R₆, OH, CH₂OH, N(R₆)₂ or halogen; R₁₄ is independently hydrogen, C₁₋₁₀ alkyl,XC₁₋₁₀ alkyl, Ar or XAr; R₁₅ is independently C₁₋₆ alkyl,cyclopropylmethyl, cyclopropylethyl or phenyl substituted by one or twoC₁₋₆ alkyl, OH, C₁₋₅ alkoxy, S(O)_(q) R₆, N(R₆)₂, Br, F, I, Cl, CF₃ orNHCOR₆ ; X is independently (CH₂)_(n), O, NR₆ or S(O)_(q) ; X' isindependently O, NR₆ or S(O)_(q) ; Y is independently CH₃ or X(CH2)_(n)Ar; Ar is: ##STR16## both of which may be unsubstituted or substitutedby one or two Z₁ or Z₂ groups; A is independently C═O, or (C(R₆)₂)_(m) ;B is independently --CH₂ -- or --O--; Z₁ and Z₂ are independentlyhydrogen, XR₆, C₁₋₈ alkyl, C₁₋₆ alkoxy, (CH₂)_(q) CO₂ R₆, C(O)N(R₆)₂,CN, (CH₂)_(n) OH, NO₂, F, Cl, Br, I, N(R₆)₂, NHC(O)R₆, O(CH₂)_(m)C(O)NR_(a) SO₂ R₁₅, (CH₂)_(m) OC(O)NR_(a) SO₂ R₁₅, or O(CH₂)_(m) R_(a)C(O)NR_(a) SO₂ R₁₅ ; m is independently 1 to 3; n is independently 0 to6; q is independently 0, 1 or 2; provided R₃, R₄ and R₅ are notO--O(CH₂)_(n) Ar or O--OR₆ ; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 wherein P is CO₂ R₆ ; R₁ is hydrogen;R₂ is Ar, cyclohexyl or C₁₋₄ alkyl; R₃ and R₅ are independentlyhydrogen, CO₂ R₆, OH, C₁₋₈ alkoxy, C₁₋₈ alkyl, N(R₆)₂, NO₂, Br, F, Cl,I, R₁₃ CO₂ R₇, X(CH₂)_(n) R₈, (CH₂)_(m) X'R₈, or X(C(R₆)₂)_(m) OR₆ ; R₄is hydrogen, OH, C₁₋₅ alkoxy, N(R₆ 2, Br, F, Cl, I, NHCOCH₃, or S(O)_(q)C₁₋₅ alkyl wherein the C₁₋₅ alkyl may be unsubstituted or substituted byOH, methoxy or halogen; R₆ is hydrogen, methyl or ethyl; R₇ is hydrogen,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, all of which may beunsubstituted or substituted by one or more OH, N(R₆)₂, CO₂ R₁₂,halogen, or R₇ is (CH₂)_(n) Ar wherein n is zero or 1 and Ar issubstituted phenyl; R₁₁ is hydrogen, phenyl, C₁₋₈ alkyl, C₂₋₈ alkenyl,or C₂₋₈ alkynyl, all of which may be substituted or unsubstituted by oneor more OH, CH₂ OH, N(R₆)₂, or halogen; R₁₂ is hydrogen or C₁₋₆ alkyl;R₁₃ is phenyl or C₂₋₁₀ alkylene, all of which may be unsubstituted orsubstituted by one or more CO₂ R₆, OH, CH₂ OH, N(R₆)₂, or halogen; andR₁₅ is hydrogen or C₁₋₆ alkyl.
 3. A compound of claim 2 wherein P is CO₂H; R₁ is hydrogen; R₂ is a group Ar wherein Ar is a group (a) or (b) andin said group (a) or (b), Z₁ and Z₂ are independently hydrogen, CO₂ R₆,(CH₂)_(n) OH, C₁₋₄ alkyl or C₁₋₆ alkoxy and A is CH₂, and one or both Bsare O; R₃ is Br, Cl, C₁₋₈ alkoxy or X(CH₂)_(n) R₈, wherein X is O, n is0, 1, or
 2. and R₈ is selected from: CO₂ H, OH, CONR₇ SO₂ R₁₁ wherein R₇is H or C₁₋₈ alkyl, R₁₁ is C₁₋₈ alkyl or phenyl optionally substitutedby Br, Cl, F, or C₁₋₈ alkyl; or R₈ is phenyl substituted by one or moreBr, Cl, CO₂ H, CH₂ OH; R₅ is methoxy or N(R₆)₂ wherein R₆ is H ormethyl; R₄ is hydrogen; R₆ is hydrogen, methyl or ethyl; R₇ is hydrogen,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, all of which may beunsubstituted or substituted by one or more OH, N(R₆)₂, CO₂ R₁₂,halogen, or R₇ is (CH₂)_(n) Ar wherein n is zero or 1 and Ar is phenylsubstituted or unsubstituted by halogen or C₁₋₅ alkoxy; R₁₂ is hydrogenor C₁₋₆ alkyl; R₁₃ is phenyl, pyridyl, or C₂₋₁₀ alkylene, all of whichmay be unsubstituted or substituted by one or more CO₂ R₆, OH, CH₂ OH,N(R₆)₂, or halogen; and R₅ is hydrogen, ethyl, isopropyl, n-butyl,cyclopropylmethyl or cyclopropylethyl.
 4. A pharmaceutical compositioncomprising a compound of claim 1 and a pharmaceutically acceptablecarrier.
 5. A method of treatment of diseases caused by an excess ofendothelin comprising administering to a subject in need thereof, aneffective amount of an endothelin receptor antagonist of claim
 1. 6. Amethod of treating renal failure or cerebrovascular disease whichcomprises administering to a subject in need thereof, an effectiveamount of a compound of claim
 1. 7. A method for the prophylaxis andtreatment of radiocontrast induced renal failure which comprisesadministering to a subject in need thereof, an effective amount of acompound of claim
 1. 8. A method of treatment of congestive heartfailure which comprises administering to a subject in need thereof, aneffective amount of a compound of claim
 1. 9. A method of treatment ofunstable angina, coronary vasospasm and myocardial salvage whichcomprises administering to a subject in need thereof, an effectiveamount of a compound of claim
 1. 10. A method of preventing or treatingrestenosis which comprises administering to a subject in need thereof,an effective amount of a compound of claim
 1. 11. A method of treatmentof pulmonary hypertension which comprises administering to a subject inneed thereof, an effective amount of a compound of claim
 1. 12. A methodof treatment of stroke or subarachnoid hemorrhage which comprisesadministering to a subject in need thereof, an effective amount of acompound of claim
 1. 13. A process for preparing a compound of Formula(I) of claim 1 by:(a) Reaction of a compound of Formula (II) ##STR17##or a protected form or precursor thereof with a compound of Formula (7)##STR18## R^(a) is independently hydrogen or C₁₋₆ alkyl; R₁ isindependently hydrogen Ar, C₁₋₆ alkyl or C₁₋₆ alkoxy; R₂ is Ar, C₁₋₈alkyl, C(O)R₁₄ or ##STR19## R₃ and R₅ are independently hydrogen, CO₂R₆, OH, R₁₃, OH, C₁₋₈ alkyl, S(O)_(q) R₁₁, N(R₆)₂, NO₂, Br, F, I, Cl ,CF₃, NHCOR₆, R₁₃ CO₂ R₇, --X--R₉ --Y, --X(C(R₆)₂)OR₆, --(CH₂)_(m) XR₈ or--X(CH₂)_(n) R₈ wherein each methylene group within --X(CH₂)_(n) R₈ maybe unsubstituted or substituted by one or two --(CH₂)_(n) Ar groups; R₄is independently hydrogen, R₁₁, OH, C₁₋₅ alkoxy, S(O)_(q) R₁₁, whereinR₁₁ is C₁₋₅ alkyl it may be unsubstituted or substituted by OH, methoxyor halogen; N(R₆)₂, Br, F, I, Cl or NHCOR₆, wherein the C₁₋₅ alkoxy maybe unsubstituted or substituted by OH, methoxy or halogen; D is O; n isindependently 0 to 6; and m is independently 1 to 3; and (b) optionalsaponification of the ester group; (c) optional salt formation.
 14. Acompound of claim 1 selectedfrom:E-3-[3-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-fur-2-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoicacid, andE-3-[4-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-fur-3-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoicacid.